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This is a very exciting study that defines a molecular mechanism for the long-known association of cancer with chronic inflammation.

The authors identify an inflammatory positive feedback loop within cancer cells that is critical for transformation, without a requirement for genetic mutations. Key...
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This is a very exciting study that defines a molecular mechanism for the long-known association of cancer with chronic inflammation.

The authors identify an inflammatory positive feedback loop within cancer cells that is critical for transformation, without a requirement for genetic mutations. Key players in this network are nuclear factor kappa B (NF-kB), interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT-3), which are relevant in a variety of human cancers. This paper opens up a new and exciting field of investigation. This study fits with previous work that showed that NF-kB and STAT-3 can be important in transformation and establishes that an inflammatory loop involving these proteins can be a very early event in transformation.

The authors of this impressive paper provide convincing evidence in support of a novel feedback loop that helps to explain the role of inflammation in cellular transformation. An initial transcriptional response locks key transcriptional and post-transcriptional regulatory factors in a cycle that promotes...
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The authors of this impressive paper provide convincing evidence in support of a novel feedback loop that helps to explain the role of inflammation in cellular transformation. An initial transcriptional response locks key transcriptional and post-transcriptional regulatory factors in a cycle that promotes transformation independent of the trigger, thus constituting an epigenetic switch.

Current studies have shown a correlation between an increase in inflammatory factors and the occurrence of certain types of cancer {1-3} -- the inflammatory factors are thought to provide the growth signals required for cancer development. Until this publication, a molecular link between the inflammatory pathway and cell transformation had been elusive. Here, the authors show that transient activation of the Src-kinase oncoprotein results in cellular transformation via a cascade of gene expression changes that ultimately result in a positive feedback loop that favors the transformed state. Using a battery of loss and gain of function tests, the authors demonstrate that Src activation promotes an inflammatory response initiated by nuclear translocation of nuclear factor (NF)-kappaB. The NF-kappaB transcription factor directly up-regulates transcription of Lin28, which negatively regulates the expression of let-7 miRNA. Down-regulation of let-7 miRNA is a critical step in the transformation pathway, as the authors provide evidence in support of interleukin (IL)6 as a new target of let-7: its mRNA contains a binding site in its 3'UTR, the IL6 luciferase reporter is sensitive to let-7, and let-7 transcripts can be immunoprecipitated by an Argonaute antibody. Thus, decreased let-7 results in increased IL6, which in turn activates STAT3, a transcription factor that promotes oncogenic pathways. IL6 also positively regulates NF-kappaB, indirectly maintaining its own expression by assuring low levels of let-7 miRNA. Perturbation of the expression of any of the factors involved in the inflammatory and cell transformation response shows that these genes are all required for tumor growth in this system. This work elegantly defines a positive feedback loop that involves NF-kappaB, Lin28, let-7, IL6 and STAT3, and helps to elucidate the molecular mechanisms that link inflammation to oncogenesis.

Although there is an undeniable association between inflammation and carcinogenesis, the molecular mechanisms that occur in the transition from one process to the other are largely unknown. lliopoulos et al. present in this elegant study mechanistic evidence of this association and provide a rationale...
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Although there is an undeniable association between inflammation and carcinogenesis, the molecular mechanisms that occur in the transition from one process to the other are largely unknown. lliopoulos et al. present in this elegant study mechanistic evidence of this association and provide a rationale for future approaches aimed at targeting inflammatory processes during carcinogenesis.

The authors report how a transient activation of an oncogenic signal is able to induce an epigenetic switch that transforms normal cells into neoplastic ones. Specifically, they show that the temporary activation of the Src oncogene in non-transformed cancer cells triggers an inflammatory response mediated by the transcription factor nuclear factor-kappa B (NF-kB). This first step decreases the expression of let-7 microRNA by inducing the transcription of Lin28B. As a result of let-7 inhibition, interleukin 6 (IL6), a target of this microRNA, increases its expression and promotes cellular transformation through signal transducer and activator of transcription 3 (STAT3), a transcriptional effector of this interleukin signaling. Finally, IL6 activates NF-kB, creating a positive feedback loop involving these components (NF-kB-Lin28B-let-7-IL6). This loop explains why the transformed phenotype is maintained in the absence of the oncogene activity. Interestingly, the inhibition of any of the components of the signaling loop leads to loss of the transformed state, providing a new experimental model of oncogenesis. Overall, this manuscript provides important findings related to inflammation-mediated carcinogenesis and opens up the possibility of developing new options for the treatment of tumors by interfering with the inflammatory feedback loop. This could be potentially useful for gastrointestinal tumors since the molecules participating in this regulatory signaling network are considered to have a prominent role in the genesis of these diseases.

Acknowledgments

I would like to thank Emma Folch-Puy for their assistance in the preparation of this evaluation.

Using immortalized human breast epithelial cells that express a conditionally activated mutant of Src kinase, the authors identify a positive feedback loop that constitutes an epigenetic switch leading to stable transformation of cells.

More specifically, a transient boost in Src activity engages this...
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Using immortalized human breast epithelial cells that express a conditionally activated mutant of Src kinase, the authors identify a positive feedback loop that constitutes an epigenetic switch leading to stable transformation of cells.

More specifically, a transient boost in Src activity engages this positive feedback loop that involves nuclear factor kappaB (NF-kB), which increases expression of Lin28B and thereby suppresses the level of the let7 family of microRNAs, which attenuate the level of interleukin-6 (IL-6). The resultant increase in IL-6 enforces activation of NF-kB, and thereby establishes the positive feedback loop. These in vitro observations appear to extend to human disease, since there is an inverse relationship between the level of let-7a and IL-6 in certain types of human tumors. Finally, the discoveries outlined in this report substantially advance our molecular understanding of the relationship between inflammation and cancer.

Inflammation is linked clinically and epidemiologically to cancer, and NF-kappaB appears to play a causative role, but the mechanisms are poorly understood. We show that transient activation of Src oncoprotein can mediate an epigenetic switch from immortalized breast cells to a stably transformed line that forms self-renewing mammospheres that contain cancer stem cells. Src activation triggers an inflammatory response mediated by NF-kappaB that directly activates Lin28 transcription and rapidly reduces let-7 microRNA levels. Let-7 directly inhibits IL6 expression, resulting in higher levels of IL6 than achieved by NF-kappaB activation. IL6-mediated activation of the STAT3 transcription factor is necessary for transformation, and IL6 activates NF-kappaB, thereby completing a positive feedback loop. This regulatory circuit operates in other cancer cells lines, and its transcriptional signature is found in human cancer tissues. Thus, inflammation activates a positive feedback loop that maintains the epigenetic transformed state for many generations in the absence of the inducing signal.

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